ABSTRACT The goal of this proposal is to develop tumor necrosis factor ? (TNF?)-inhibiting compounds as neuroprotectant drugs for treating Alzheimer?s disease (AD). Current FDA-approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression. Thus, a critical need exists for a novel AD treatment directed towards AD pathophysiology. Recent studies implicate the neuroinflammatory cytokine TNF-? as a key mediator in AD- associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNF? is a ?druggable? molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound shows potent TNF? inhibition in vitro. Our Phase 1 SBIR studies demonstrate that our small molecule TNF? inhibitor administered orally every day for 10 months significantly improved cognitive function in the triple-transgenic (3xTg) AD mouse model. Our compound also modulated brain TNF? protein levels and halted the progress of AD-associated neuropathology including A plaques and neurofibrillary tangles as assessed by immunohistological staining. No morbidity, mortality or any obvious side effects were observed despite the long-term oral daily treatment regimen with our compound. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed studies are following up on recently awarded phase 2 SBIR where we are performing several key FDA-required IND studies. The proposed CRP grant studies will build on the phase 2 SBIR studies to lead to an IND submission. Key Aims include large animal safety toxicology studies and preparation for Pre-IND meeting with the FDA.